1. Field of the Invention
This invention relates to the field of pharmaceutical compounds, and to the sub-field of psychopharmacologically active compounds. The compounds in question show an inhibition of the extinction of conditioned flight behaviour, as a result of which they are eminently suitable for the treatment of mental disorders in which a stimulation of the cerebral function is desired, such as in case of senility. The invention further relates to pharmaceutical compositions containing these peptide compounds or their derivatives where the latter are an active constituent.
2. Description of the Prior Art
From EUROPEAN JOURNAL OF PHARMACOLOGY 2, 14 (1967) it is known that the natural adrenocorticotropic hormone (ACTH), and more specifically certain peptide fragments thereof, retard the extinction of the so-called "conditioned flight behaviour". In particular, the peptide containing the amino-acid sequence 4-10 from ACTH proved to be the smallest peptide fragment which was as active as ACTH itself in this respect.
From the U.S. Pat. No. 3,853,836 it appears, however, that the complete amino-acid sequence 4-10 ACTH is not essential for psychopharmacological activity but that a much shorter peptide, namely, 4-6 ACTH, is responsible for this activity. It furthermore appears that the N-terminal amino-acid L-Met may be replaced without loss of activity by D-Met, L- or D-Met (.fwdarw. O), L- or D-Met (.fwdarw. O.sub.2), desamino-Met, desamino-Met (.fwdarw. O), desamino-Met (.fwdarw. O.sub.2) or by the group ##STR1## where Q represents an alkylidene moiety having from one to about six carbon atoms or an alkylene moiety having from one to about six carbons.
It is furthermore taught in U.S. Pat. No. 3,856,770 that the replacement of the C-terminal peptide residue -L-Trp-Gly-OH of the original 4-10 ACTH peptide by one of the groups consisting of -L-Phe-OH, L-Phe-Gly-OH, a phenylalkylamino moiety or a (3-indolyl) alkylamino moiety results in an increase in psychopharmacological activity.
It is further reported in the U.S. Pat. No. 3,842,064 that a considerable increase in psychopharmacological activity is obtained on replacing the amino-acid L-arginine (L-Arg) in the original 4-10 ACTH peptide (or in one of the modified peptides described in the above-noted patent specifications) by D-lysine (D-Lys).
One of the most active peptides named in the above-noted U.S. Patents is the peptide represented by the abbreviation: EQU 4-9 ACTH, 4-L-Met (.fwdarw. O), 8-D-Lys, 9-L-Phe,
a peptide which with respect to the original 4-9 ACTH has been changed in accordance with the potentiation noted in the patent specifications in positions 4, 8 and 9.
This peptide, to wit EQU H-L-Met (.fwdarw. O)-L-Glu-L-His-L-Phe-D-Lys-L-Phe-OH,
proves to be about 1000 times as active as the unchanged 4-9 ACTH.
It has now been found that the peptide-fragment of this 4-9 ACTH, 4-L-Met(.fwdarw. O), 8-D-Lys, 9-L-Phe, to wit the fragment: EQU L-Phe-D-Lys-L-Phe
in itself also occasions some psychopharmacological activity, although in a latent form. On the basis of U.S. Pat. No. 3,856,770 and U.S. Pat. No. 3,842,064 it is recognized by those skilled in the art that a highly active peptide is(was) obtained by lengthening the chain of the peptide L-Phe-D-Lys-L-Phe at the N-terminal end, for example, with the peptide fragment L-Met(.fwdarw. O)-L-Glu-L-His: EQU L-Met(.fwdarw. O)-L-Glu-L-His-L-Phe-D-Lys-L-Phe
Surprisingly, it has now also been found that highly active peptides can be obtained by lengthening the chain at the C-terminal end of the peptide L-Phe-D-Lys-L-Phe. This pronounced potentiation (with a factor of at least 1000) on lengthening the chain at the C-terminal end was not to be expected to those skilled in the art on the basis of the information known until now. (It has after all been shown that C-terminal chain prolongation of the original 4-10 or 4-9 ACTH resulted in no potentiation of effect whatsoever - see e.g. European Journal of Pharmacology 2, 14 (1967) - while it turned out that C-terminal chain prolongation of the 7-9 ACTH peptide increased the activity at most by a factor 10. This surprising activity can be illustrated by means of the example given in the table below:
TABLE I __________________________________________________________________________ Potency Ratio with Respect to 4-10 Peptide ACTH __________________________________________________________________________ Met-Glu-His- Phe-Arg-Trp (4-9 ACTH) 1 2. Phe-Arg-Trp (7-9 ACTH) 0.1 3. Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys 1 (7-16 ACTH) 4. Phe-D-Lys-Phe 0.1 5. Phe-D-Lys-Phe-Gly-Lys-Pro-Val-Gly-Lys-Lys 100 __________________________________________________________________________
Furthermore, we demonstrated that the lengthening of the chain at the C-terminal end of the above peptide L-Phe-D-Lys-L-Phe proved to be of high significance in the sense that a minimum C-terminal chain length is essential. This minimum lengthening of the chain proved surprisingly to be the peptide 10-16 ACTH; a shorter chain length reduced the activity to a level corresponding to that seen with unaltered 7-16 ACTH.
We furthermore surprisingly found that a still more considerable potentiation could be achieved by replacing the amino-acid L-Lys (position 11) in the minimum essential C-terminal chain lengthening (10-16 ACTH) by the amino-acid D-Lys. This modification increases the activity of the peptide by a further factor of 100. These facts are clearly illustrated by the following example in table II:
TABLE II ______________________________________ Potency Ratio with Respect to 4-10 Peptide ACTH ______________________________________ 1. Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys 1 (7-16 ACTH) 2. Phe-D-Lys-Phe-Gly-Lys-Pro-Val-Gly-Lys-Lys 100 3. Phe-D-Lys-Phe-Gly-Lys-Pro-Val-Gly-Lys 1 4. Phe-D-Lys-Phe-Gly-D-Lys-Pro-Val-Gly-Lys-Lys 10,000 ______________________________________
The peptide L-Phe-D-Lys-L-Phe, the activity of which may be substantially increased as stated above by lengthening the C-terminal chain, may be further potentiated by additional N-terminal chain lengthening in methods described in U.S. Pat. No. 3,853,836, U.S. Pat. No. 3,856,770, and U.S. Pat. No. 3,842,064, which methods and specific additional lengths are incorporated herein by reference as if copied verbatim. The resultant peptides prove to possess psychopharmacological activity which is 10.sup.6 to 10.sup.7 times as strong as that of the original 4-10 ACTH peptide.
It has furthermore been found that the first amino-acid Phe in the original L-Phe-D-Lys-L-Phe does not necessarily have to be present, but it may also be replaced by numerous other amino-acids, so that the primary advantages of this amino-acid evidently come from the provision of the additional right chain length.